DESCRIPTION: The neuropeptide somatostatin (SST) is recognized as a major neurotransmitter system with important regulatory functions in the nervous system and elsewhere. SST acts by signaling through a family of five G protein coupled receptors. Profound disturbances in SST function have been implicated in several neurodegenerative diseases including Alzheimer's Disease (AD), Huntington's Disease (HD), hypoxia-ischemia, and AIDS encephalopathy. For instance, in AD, cortical and CSF concentrations of SST are selectively reduced. By contrast, in HD, striatal SST levels are increased and the subset of striatal SST-producing neurons have been found to be selectively resistant to neurodegeneration. These neurons colocalize the neuropeptide NPY and nitric oxide synthase. The process of selective sparing of these specialized SST-producing neurons appears to be a feature of several neurodegenerative conditions. Increasing evidence from our laboratory has implicated SST as a potent neuroprotective agent in disease models of neurodegeneration. We hypothesize that somatostatinergic neurons respond to a variety of neurotoxic insults by inducing SST gene expression and peptide production to provide neuroprotection, and that in order to play this important role, the SST-producing neurons are themselves selectively resistant to neurotoxicity. A important mechanism through which SST mediates neuroprotection is suggested to be the abrogation of intracellular calcium entry, a key event that triggers cell death. Our long-term goal is to define the functional role of SST and its five receptors in the molecular pathogenesis of neurodegeneration. Using both in vitro neuronal culture systems as well as in vivo models, our specific objectives are (i) to investigate a general role for SST in neuroprotection; (ii) to identify the SST receptor subtype(s) that mediate(s) neuroprotection; (iii) to determine whether SST neuroprotection is due to a receptor-induced reduction in intracellular Ca2+; and (iv) to identify the molecular mechanisms for upregulated SST function by the SST-producing neurons. These studies will provide new insights into the neurobiology of SST and the mechanism of SST-mediated neuroprotection, and open the door to the rational design of subtype selective SST compounds for the future treatment of neurodegenerative disorders.